Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer’s disease

Damjanac, Milena; Bilan, Agnès Rioux; Pocard, Marc; Pontcharraud, Raymond; Fauconneau, Bernard; Hugon, Jacques; Page, Guylène

doi:10.1016/j.nbd.2007.09.008

Cited by 30 publications

(25 citation statements)

References 63 publications

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“…In these APPswePS1dE9 mice, a large decrease of the activation of mTOR and its downstream substrate p70S6K was observed according to previous findings in other transgenic mouse AD models [60-63]. However, in some transgenic mouse models of AD, the mTOR activation was not modified while the p70S6K activation decreased [64]. In two independent mouse models of AD, rapamycin, through inhibition of mTOR signaling, rescued cognitive deficits by suppressing extracellular Aβ deposition and intracellular tau accumulation [45,63].…”

Section: Discussionsupporting

confidence: 75%

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice

Audigier

Bilan

Quellard

et al. 2014

J Neuroinflammation

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BackgroundIn recent years, studies have sought to understand the mechanisms involved in the alteration of autophagic flux in Alzheimer's disease (AD). Alongside the recent description of the impairment of lysosomal acidification, we wanted to study the relationships between inflammation and autophagy, two physiological components deregulated in AD. Therefore, a longitudinal study was performed in APPswePS1dE9 transgenic mice at three, six and twelve months of age.MethodsAutophagic markers (Beclin-1, p62 and LC3) and the activation of mammalian Target of Rapamycin (mTOR) signaling pathway were quantified by western blot. Cytokine levels (IL-1β, TNF-α and IL-6) were measured by ELISA. Transmission electron microscopy was performed to detect autophagic vacuoles. Mann-Whitney tests were used to compare wild-type (WT) versus APPswePS1dE9 mice. Longitudinal changes in parameters were analyzed with a Kruskal-Wallis test followed by a post-hoc Dunn’s test. Correlation between two parameters was assessed using a Spearman test.ResultsCompared to 12-month old WT mice, 12-month old APPswePS1dE9 mice had higher levels of IL-1β and TNF-α, a greater inhibition of the mTOR signaling pathway and lower levels of Beclin-1 expression both in cortex and hippocampus. Regarding the relationship of the various parameters in 12-month old APPswePS1dE9 mice, Beclin-1 rates were positively correlated with IL-1β and TNF-α levels. And, on the contrary, TNF-α levels were inversely correlated with the levels of mTOR activation. Altogether, these results suggest that inflammation could induce autophagy in APPswePS1dE9 mice. However, these transgenic mice displayed a large accumulation of autophagic vesicles within dystrophic neurons in cortex and hippocampus, indicating a terminal failure in the autophagic process.ConclusionsThis first demonstration of relationships between inflammation and autophagy in in vivo models of AD should be taken into account in new therapeutic strategies to prevent inflammation and/or stimulate autophagy in advanced neurodegenerative process such as AD.

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Section: Discussionsupporting

confidence: 75%

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice

Audigier

Bilan

Quellard

et al. 2014

J Neuroinflammation

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“…The increase in inactivating phosphoS9 of GSK3β (Tau kinase 1) in these reports does not explain how tau is overphosphorylated in AD. Some studies in fact show basal or stimulated mTOR and Akt are deactivated or unchanged in various transgenic and experimental AD models [48, 50–52, 97]. Our finding that rapamycin in beneficial (regardless of mTOR basal activation status) is consistent with results that mTOR inhibition ameliorates cognitive deficits and pathology in AD mice [44,46] and disease manifestations and proteotoxicity in other neurodegenerative models [97, 98].…”

Section: Discussionsupporting

confidence: 89%

“…Moreover, APP(swe)/PS1(deltaE9) transgenic mice display increased autophagic activity accompanied by decreased mTOR activity [49]. In yet another transgenic model, APP(s1)/PS1(KI), while mTOR itself was unchanged, downstream activation of p70S6K (pT389) was reduced rather than stimulated [50]. Consistent with these, but using a growth factor stimulation paradigm in rat PCNs, Aβ treatment inhibited BDNF-induced, Akt-mTOR signal activation [51].…”

Section: Introductionmentioning

confidence: 99%

mTORC2 (Rictor) in Alzheimer’s Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons

Lee

Kwon

Lemere

et al. 2017

JAD

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Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer’s disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42, mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD.

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“…The immunofluorescence protocol for mouse brain sections was performed as previously described (22). 4-m sagittal sections were first incubated 2 h at room temperature with the monoclonal mouse primary antibody to ␤-amyloid (4G8) at 1:100.…”

Section: Methodsmentioning

confidence: 99%

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

Couturier

Morel

Pontcharraud

et al. 2010

Journal of Biological Chemistry

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Alzheimer Disease (AD)2 is the leading cause of dementia in the elderly, affecting 25 million people in the world with about 5% of genetic origin. The biological features of AD are neuronal loss, senile plaques predominantly composed of amyloid ␤ peptide (A␤), and the presence of neurofibrillary tangles, leading to a progressive deterioration of cognitive function with loss of memory. Unfortunately, no definitive therapy for AD exists.The involvement of A␤ is clearly established, but mechanisms that underlie neuronal death are currently under investigation. For 10 years, research has focused on pathways controlling translation (1-5). They revealed that activated double-stranded RNA-dependent protein kinase (PKR), which phosphorylates the ␣-subunit of eIF2, was associated with degenerating neurons in AD brains (6 -8). Furthermore, the levels of phosphorylated forms of PKR and eIF2␣ were significantly increased in AD cellular models exposed to A␤42 (2, 5) in the brain of AD transgenic mice (1, 9) and in lymphocytes of AD patients (10). These modifications were negatively correlated with cognitive and memory test scores performed in AD patients (3, 10, 11). Besides its important role as a translational regulator, PKR is a key mediator in different signaling pathways. Indeed, among its downstream targets, the Fas-associated protein with a death domain (FADD) and subsequent caspase-8 are responsible for PKR-induced apoptosis in virus-infected cells (12). Furthermore, the overexpression of a dominant-negative FADD construct rescued SH-SY5Y cells from either tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or A␤-induced neurotoxicity (13). FADD could be involved in apoptosis through its nuclear localization by interacting with the methylCpG binding domain protein 4 (MDB4), a protein known to be implicated in DNA repair, but that could promote apoptosis when associated with FADD (14). Furthermore, many postmortem studies have reported the role of the FADD-linked death receptor signaling pathway in the pathobiology of AD (15-17).However, control of FADD under the PKR activation in AD remains unknown. The present study performed a detailed analysis of PKR and FADD interaction in A␤-treated cells and in APP SL PS1 KI transgenic mice. The purpose is to determine if inhibition of PKR could reduce apoptosis through the decrease in this death adaptor activation. Here, we showed a physical interaction between PKR and FADD in nuclei of A␤42-treated SH-SY5Y and in APP SL PS1 KI mice. Furthermore, PKR inhibitory treatments prevented not only the nuclear translocation of FADD but also significantly decreased caspase-3 and -8 activities induced by A␤ neurotoxicity. EXPERIMENTAL PROCEDURES

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Dissociation of Akt/PKB and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer’s disease

Cited by 30 publications

References 63 publications

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice

mTORC2 (Rictor) in Alzheimer’s Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

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